A major concern in HIV pathogenesis is the establishment of long-term reservoirs of replication-competent virus. Although much attention has been directed to the latently infected T cell reservoir of HIV, less is known about the reservoir of infectious virus on follicular dendritic cells (FDC). FDCs trap and retain large quantities of HIV and throughout much of disease, viral replication persists in secondary lymphoid tissues surrounding germinal centers where FDCs reside. Our working hypothesis is that FDC represent a dangerous, long-term reservoir of highly infectious HIV. Our previous work indicated that HIV trapped on FDC as immune complexes is infectious and that FDC permit infection by this virus even in the presence of large amounts of otherwise neutralizing antibodies. During the previous finding period, we extended this work and found that FDC maintain HIV in an infectious state for many months in the complete absence of virus replication. Furthermore, FDCs potentiate the amount of HIV infection/replication in CD4 T cell cultures and at least part of this effect is attributable to FDC sparing of bystander T cells from undergoing HIV-induced apoptosis. We propose to extend this work and examine other contributions of FDCs that increase infection as well as to characterize FDC-HIV binding interactions. This proposal seeks to determine the mechanism(s) used by FDC to augment HIV infection/replication in CD4-bearing T cells (aim 1). We also seek to determine if FDC can "archive" infectious HIV while being exposed to mutants or new populations of HIV(aim 2). Finally, we seek to determine if the FDC reservoir can be destroyed and, if so, to examine the fate of FDC-trapped virus (aim 3). Because virus replication continues even under HAART, we reason that HIV on FDCs is constantly replenished and this virus could cause re-infection on cessation of drug or other selective therapy. A better understanding of HIV-FDC interactions should help in designing intervention strategies that effectively target this important reservoir.